WO2011105643A1

WO2011105643A1 - Selenalzole derivative having ligand which activates peroxisome proliferator activated receptor (ppar), preparing method thereof and usage of the chemical compounds

Info

Publication number: WO2011105643A1
Application number: PCT/KR2010/001204
Authority: WO
Inventors: 강헌중; 진정욱; 이재환
Original assignee: 서울대학교산학협력단
Priority date: 2010-02-25
Filing date: 2010-02-25
Publication date: 2011-09-01
Also published as: AU2010347183A1; CA2789458A1; US20120316346A1; CN102781924A; RU2510394C1; EP2540711A1; BR112012021515A2; EP2540711A4; JP2013525267A

Abstract

The present invention is related to a new selenazole derivative which activates a peroxisome proliferator activated receptor (hereinafter referred to as "PPAR"), hydrates thereof, solvates thereof, stereo isomers thereof, pharmaceutically acceptable salts thereof; a preparation method thereof; and a medicinal composition, a cosmetic product composition, functional food, functional beverage, animal feed composition, and all of which comprise the new selenazole derivative.

Description

Peroxysomal Proliferator Activating Receptor Ligand Seleazole Derivatives, Methods for Making the Same, and Uses of These Compounds

The present invention relates to a selenazole derivative compound of formula (I), a hydrate thereof, and a solvent thereof, which is a Peroxysome Proliferator Activated Receptor (PPAR) activating ligand that can be used for the treatment of obesity, hyperlipidemia, fatty liver, arteriosclerosis and diabetes. A cargo, stereoisomers thereof, pharmaceutically acceptable salts thereof, and pharmaceuticals, cosmetic compositions, functional foods, functional beverages, and animal feed compositions comprising the same.

[Formula I]

Among the nuclear receptors, the Peroxysome Proliferator Activated Receptor (PPAR) has three known subtypes: PPARα, PPARγ, and PPARδ ( Nature , 1990 , 347 , p645-650., Proc. Natl. Acad. Sci. USA 1994 , 91 , p7335-7359). PPARα, PPARγ and PPARδ have distinct functions according to tissues in vivo, and expression sites also differ. PPARα is mainly expressed in the heart, kidneys, skeletal muscle, and large intestine ( Mol. Pharmacol. 1998 , 53 , p14-22., Toxicol. Lett. 1999 , 110 , p119-127, J. Biol. Chem. 1998 , 273 , p16710-16714), and β-oxidation of peroxisome and mitochondria ( Biol. Cell. 1993 , 77 , p67-76., J. Biol. Chem. 1997 , 272 , p27307-27312) . PPARγ is weakly expressed in skeletal muscle, but is expressed in large amounts in adipose tissue, and is known to be involved in the differentiation and energy storage of adipocytes in the form of fat and the regulation of insulin and sugar homeostasis ( Moll. Cell. 1999 , 4 , p585-594., p597-609., p611-617). PPARδ is evolutionarily conserved in mammals, including humans, and vertebrates such as rodents and sea lions. To date, PPARβ ( Cell 1992 , 68 , p879-887) has been found in Xenopus laevis , NUCI ( Mol. Endocrinol. 1992 , 6 , p1634-1641), PPARδ ( Proc. Natl. Acad. Sci. USA 1994 , 91 , p7355-7359), NUCI ( Biochem. Biophys. Res. Commun. 1993 , 196 , p671-677), FAAR ( J. Bio. Chem. 1995 , 270 , p2367-2371), etc. Although recently known as PPARδ, the name has been unified. In humans, PPARδ is known to be present in chromosome 6p21.1-p21.2. In rats, PPARδ mRNA is found in cells of various sites, but the amount is lower than that of PPARα or PPARγ ( Endocrinology 1996 , 137 , p354-). 366., J. Bio. Chem. 1995 , 270 , p2367-2371, Endocrinology 1996 , 137 , p354-366). So far, according to a study PPARδ is known to play an important role in expressing the process of germ cells (Genes Dev 1999, 13, p1561-1574 ..), The central nervous system: the differentiation of nerve cells (Central Nervous System CNS) (J Chem. Neuroanat 2000 , 19 , p225-232), wound healing through anti-inflammatory effects ( Genes Dev. 2001 , 15 , p3263-3277, Proc. Natl. Acad. Sci. USA 2003 , 100 , p6295-6296), etc. It has been reported to perform its physiological function. Recent studies have demonstrated that PPARδ is involved in adipocyte differentiation and fat metabolism ( Proc. Natl. Acad. Sci. USA 2002 , 99 , p303-308., Mol. Cell. Biol. 2000 , 20 , p5119 -5128), it was found that PPARδ activates the expression of uncoupling proteins (UCPs), a key gene involved in β-oxidation and a gene involved in energy metabolism, in fatty acid degradation, improving obesity and improving endurance ( Nature 2000 , 406 , p415-418, Cell 2003 , 113 , p159-170, PLoS Biology 2004 , 2 , e294, Cell , 2008 , 134, 405415). Activation of PPARδ also increases HDL and improves type 2 diabetes in the absence of weight change ( Proc. Natl. Acad. Sci. USA 2001 , 98 , p5306-5311, 2003 , 100 , p15924-15929, 2006 , 103 , p3444-3449), it is also possible to inhibit atherosclerosis-related genes to treat atherosclerosis ( Science , 2003 , 302 , p453-457, PNAS , 2008 , 105, 42714276). Therefore, the regulation of fat metabolism using PPARδ provides important clues needed to treat and resolve obesity, diabetes, hyperlipidemia and atherosclerosis.

It is an object of the present invention to provide novel compounds with high selective activation to PPAR δ and to provide pharmaceutical, cosmetic compositions, functional foods, functional beverages and animal feed compositions comprising the novel compounds according to the invention. .

The present invention provides a selenazole derivative compound represented by the following formula (I) having activity on a Peroxysome Proliferator Activated Receptor (hereinafter referred to as 'PPAR'), a hydrate thereof, a solvate thereof, a stereoisomer thereof, A pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical, cosmetic composition, functional food, functional beverage, and animal feed composition comprising the same.

[Formula I]

[In Formula I, A is O, NR, S, S (= 0), S (= 0) ₂ or Se;

B is hydrogen or

Is;

R ₁ is hydrogen, C ₁ -C 8 alkyl or halogen;

R ₂ is hydrogen, C 1 -C 8 alkyl,

or

ego;

X ^a and X ^b are independently of each other CR or N;

R is hydrogen or C1-C8 alkyl;

R ₃ is hydrogen, C 1 -C 8 alkyl or halogen;

R ₄ and R ₅ are independently of each other hydrogen, halogen or C1-C8 alkyl;

R ₆ is hydrogen, halogen, C 1 -C 8 alkyl, C 2 -C 7 alkenyl, allyl, alkali metal, alkaline earth metal or a pharmaceutically acceptable organic salt;

R ₂₁ , R ₂₂ , and R ₂₃ are each selected from C3-C12 containing one or more heteroatoms selected from hydrogen, halogen, CN, NO ₂ , alkyl of C1-C7, aryl of C6-C12, N, O and S. Heteroaryl, 5- or 7-membered heterocycloalkyl, or C1-C7 alkoxy group;

m is an integer from 1-4;

p is an integer from 1-5;

s is an integer from 1-5;

u is an integer of 1-3;

w is an integer from 1-4;

The alkyl and alkoxy of R ₁ , R ₃ , R ₄ , R ₅ , R ₆ , R ₂₁ , R ₂₂ and R ₂₃ may be further substituted with one or more halogen, cycloalkyl of C 3 -C 7 or alkylamine of C 1 -C 5. Can be]

R ₁ of a particularly preferred selenazole derivative of formula (I) having activity on a Peroxysome Proliferator Activated Receptor (PPAR) is hydrogen, alkyl or fluorine of C1-C5 substituted with one or more fluorine; R ₂ is hydrogen, C 1 -C 8 alkyl,

or

ego; X ^a and X ^b are independently of each other CR or N; R is hydrogen or C1-C8 alkyl; R ₃ is hydrogen, C 1 -C 5 alkyl or halogen substituted or unsubstituted; R ₄ and R ₅ are, independently from each other, hydrogen, C1-C5 alkyl, optionally substituted with halogen; R ₆ is hydrogen, alkyl of C1-C8, halogen, allyl, alkenyl of C2-C7, pharmaceutically acceptable organic salt, alkali metal or alkaline earth metal; R ₂₁ , R ₂₂ and R ₂₃ independently of one another are hydrogen, halogen, CN, NO ₂ , at least one selected from alkyl substituted or unsubstituted C 1 -C 7 alkyl, C 6 -C 12 aryl, N, O and S It is preferable that the C3-C12 heteroaryl containing a hetero atom, the 5- to 7-membered heterocycloalkyl or the halogen is a substituted or unsubstituted C1-C5 alkoxy group.

Illustrating the range of selenazole derivatives of formula I according to the invention R ₁ is independently of each other hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 2-ethyl Hexyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, pentafluoroethyl, fluorine, bromine, iodide, chlorine; R ₂ is hydrogen or substituted or unsubstituted benzyl, phenylbenzyl or pyridylbenzyl, wherein each of the phenyl, pyridyl and benzyl groups of R ₂ is fluorine, chlorine, methyl, ethyl, n-propyl, i-propyl, t- Butyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, pentafluoroethyl, methoxy, ethoxy, propyloxy, n-butoxy, t-butoxy, fluoromethoxy, difluoromethoxy, Trifluoromethoxy, 2-fluoroethoxy, pentafluoroethoxy, CN, NO ₂ , aryl of C6-C12 or C3-C12 heteroaryl containing one or more heteroatoms selected from N, O and S May be further substituted; R ₃ is hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 2-ethylhexyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, Pentafluoroethyl, fluorine, chlorine; R ₄ and R ₅ independently of one another are hydrogen, halogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 2-ethylhexyl, fluoromethyl, difluoromethyl, tri Fluoromethyl, 2-fluoroethyl, pentafluoroethyl; R ₆ is hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 2-ethylhexyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, Pentafluoroethyl, allyl, ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, pharmaceutically acceptable organic salts, Li ⁺ , Na ⁺ , K ⁺ , Ca ²⁺ , Mg ²⁺ .

The novel compounds according to the invention can be prepared via the routes of Schemes 1-5 below. Reaction Scheme 1 shows a reaction route when A is O, NR, S or Se, and Reaction Scheme 2 when A is NR, and Scheme 3 shows A when O is O.

Scheme 1

Scheme 2

Scheme 3

[Scheme 1 to 3, wherein A is O, NR, S or Se; R_One, R₂, R₃, m, p and s are the same as defined in formula (I); R_6aIs C1-C8 alkyl or allyl; R_6bIs a hydrogen atom or an alkali metal (Li⁺, Na⁺, K⁺), Alkaline earth metal (Ca²⁺, Mg²⁺) Or a pharmaceutically acceptable organic salt; Prot is a phenol protecting group, a lower alkyl group having 1 to 4 carbon atoms, allyl group, alkylsilyl or alkylarylsilyl group or tetrahydropyranyl group; X_OneIs a bromine or iodine atom; X₂AndX₃Are independently leaving groups reactive with chlorine, bromine, iodine or nucleophilic substitution.]

Formulas III-A, III-B and III-C may also be prepared via the routes of Scheme 4 below.

Scheme 4

[Wherein R ₁ , R ₂ and p are the same as defined in formula (I); R ₃₁ is C 1 -C 4 alkylsulfonyl or C 1 -C 4 alkyl substituted or unsubstituted C 6 -C 12 arylsulfonyl; R ₁₀₁ is C1-C4 alkyl; X ₂ is a leaving group that is highly reactive to chlorine, bromine, iodine or nucleophilic substitution.]

Scheme 5

EMBODIMENT OF THE INVENTION Below, the manufacturing method of this invention is demonstrated in detail.

[공정 A] 화학식 (IV-A)로 표시되는 화합물의 제조[Step A] Preparation of Compound Represented by Formula (IV-A)

In order to obtain the compound represented by the formula (IV-A), the compound represented by the formula (II) is protected with a Grignard reagent without separation process, and the organometallic reagent and sulfur (S) or After reacting selenium (Se), it is reacted with a compound of formula (III-A). This process will go through four stages of reaction in detail.

Below, a detailed process is demonstrated.

[Phenol Group Protection Reaction with Greennard Reagent]

As the anhydrous solvent used in this step, a mixed solvent in which a single solvent such as diethyl ether, tetrahydrofuran, hexane, heptane, and two or more solvents are combined. Among them, the most preferred solvent is diethyl ether, tetrahydrofuran or a mixed solvent of diethyl ether and tetrahydrofuran. Of these solvents, polar solvents are preferred, and tetrahydrofuran is most preferred.

Green Oxnard reagents used include methyl magnesium chloride, ethyl magnesium chloride, n - propyl chloride, iso - propyl magnesium chloride, n - butyl magnesium chloride, sec - butyl magnesium chloride (R ₂ MgCl) or an alkyl magnesium bromide (R ₂ MgBr )to be. Most preferred among these is iso -propylmagnesium chloride ((CH ₃ ) ₂ CHMgCl).

The reaction temperature may vary depending on the solvent used, but is usually -20 to 40 ° C., preferably 0 ° C. to room temperature (25 ° C.). The reaction time may vary depending on the reaction temperature and the solvent used, but usually 10 to 60 minutes, preferably 10 to 30 minutes.

[Halogen-lithium substitution reaction and sulfur (S) or selenium (Se) introduction reaction]

Examples of the organometallic reagent used in the halogen-lithium substitution reaction include n -butyllithium, sec -butyllithium, and tert -butyllithium. Of these, tert -butyllithium is preferable.

Sulfur (S) or selenium (Se) is preferably in the form of fine powder, dissolved in anhydrous tetrahydrofuran solvent or added or directly added to react.

The reaction temperature may vary depending on the solvent used, but is usually -78 to 25 ° C. Preferably, the halogen-metal substitution reaction is performed at -75 ° C, and the sulfur (S) or selenium (Se) introduction reaction is- Start at 75 ° C. and react at room temperature (25 ° C.). The reaction time depends on the reaction stage, halogen-metal substitution reaction is 10-30 minutes, sulfur (S) or selenium (Se) introduction reaction is 30 to 120 minutes.

[Formula (III-A) Compound Addition Reaction]

Formula (III) used in this process is synthesized according to Process H-Process K. As the halogen of the formula (III-A), chlorine, bromine and iodine elements are used, and among these, a compound of chlorine element is preferable.

The reaction temperature may vary depending on the solvent used, but is usually performed at -78 to 25 ° C, preferably at 0 to 10 ° C. The reaction time is usually 10 to 120 minutes, preferably 10 to 60 minutes or less.

[공정 B] 화학식 (V-A)로 표시되는 화합물의 제조[Step B] Preparation of Compound Represented by Formula (V-A)

In order to obtain the compound represented by the general formula (V-A), the compound represented by the general formula (IV-A) and the compound usually used as a phenol protecting group may be reacted in the presence of a base.

Lower alkyl groups, allyl groups, trimethylsilyl,tertButyldiphenylsilyl, triisopropylsilyl,tertPhenol protecting groups, such as alkylsilyl, such as -butyl dimethyl silyl, an alkylaryl silyl group, or tetrahydropyranyl group, etc. are mentioned. Among these protecting groups,tert-Butyl group, tetrahydropyranyl group, and silylated protecting group.

Examples of aprotic polar solvents used in this step include N , N -dimethylformamide, N , N -dimethylacetamide, dimethyl sulfoxide, acetonitrile, acetone, ethyl acetate, carbon tetrachloride, chloroform, dichloromethane, and the like. have. Examples of the ethers include tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, and the like. As aromatic hydrocarbon, benzene, toluene, xylene, etc. are mentioned. As the solvent used in these, an aprotic polar solvent is preferable, and N, N -dimethylformamide, chloroform and dichloromethane are more preferable.

As the base used, amine bases such as pyridine, triethylamine, imidazole, and N, N -dimethylaminopyridine are used, and the reaction of the alkyl or allyl ether protecting group includes sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like. Use as base. Of these, preferred bases are imidazole and potassium carbonate.

Tetrahydropyranyl protecting groups are obtained by catalytic reaction of 3,4-dihydro-2 H -pyran with alkyl or allyltriphenylphosphonium bromide.

The reaction temperature may vary depending on the solvent to be used, but is usually -10 to 80 ° C, preferably 0 ° C to room temperature (25 ° C). The reaction time may vary depending on the reaction temperature and the solvent used, but it is generally preferred to react within 1 hour to 1 day, preferably within 4 hours.

[공정 C] 화학식 (V-B)로 표시되는 화합물의 제조[Step C] Preparation of Compound Represented by Formula (V-B)

The compound represented by the formula (VB) is treated with a strong base of alpha-hydrogen (α-proton) of thio or selenoether from the compound of formula (VA) to prepare a nucleophile, and then reacts various electrophilic compounds. Get it done.

As the anhydrous solvent used in this step, a mixed solvent in which a single solvent such as diethyl ether, tetrahydrofuran, hexane, heptane, and two or more solvents are combined. Among these, the most preferable solvent is a mixed solvent of diethyl ether, tetrahydrofuran, diethyl ether and tetrahydrofuran.

Potassium tert -butoxide (t-BuOK), lithium diisopropyl amide (LDA), n -butyllithium, sec -butyllithium and tert -butyllithium are used as strong base reagents for the alpha-hydrogen extraction reaction. Among them, diisopropyl amide (LDA) is most preferred.

Electrophiles which react with nucleophilic compounds of thio or selenoethers are those which are readily available as known compounds or compounds which can be easily prepared according to the literature, and which contain highly reactive halogen, aldehyde and ketone groups. This is dissolved in anhydrous solvent and added or directly added to react.

The reaction temperature may vary depending on the solvent used, but is usually -78 to 25 ° C. Preferably, the alpha-hydrogen extraction reaction with a strong base is carried out at -75 ° C and the electrophilic compound is added at -75 ° C. The reaction is gradually raised to room temperature (25 ° C). The reaction time varies depending on the reaction stage, but the alpha-hydrogen extraction reaction using a strong base is carried out for 10 to 30 minutes and the reaction with the electrophilic compound for 30 to 90 minutes.

[공정 D] 화학식 (IV-B)로 표시되는 화합물의 제조[Step D] Preparation of Compound Represented by Formula (IV-B)

Compounds of formula (IV-B) are obtained as removal reactions of phenol protecting groups in compounds of formula (V-B).

Examples of the polar solvent used in this step include N , N -dimethylformamide, N , N -dimethylacetamide, dimethyl sulfoxide, acetonitrile, acetone, ethyl acetate, carbon tetrachloride, chloroform and dichloromethane. Examples of the ethers include tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, and the like. Alcohols include methanol ethanol and the like. Examples of the aromatic hydrocarbons include benzene, toluene, xylene and the like. Of these solvents, polar solvents are preferred, and tetrahydrofuran is most preferred.

Deprotection methods for phenol protecting groups include methyl, ethyl, tert -butyl, benzyl and allyl ether protecting groups, such as trimethylsilyl iodine, ethanethioalcohol sodium salt, lithium iodine, aluminum halides, boron halides, and trifluoroacetic acid. Lewis acids are used, trimethylsilyl, tert - butyl-diphenyl-silyl, triisopropylsilyl, tert - butyldimethylsilyl screen saver is tetrabutylammonium fluoride (Bu ₄ N ⁺ F ^-), such as a silyl group, a halogen acid (hydrofluoric acid Fluorides such as hydrochloric acid, hydrobromic acid) and potassium fluoride. Of these, fluoride is preferable as the method for the deprotection group reaction of the silyl group, and more preferably tetrabutylammonium fluorine is used.

The reaction temperature may vary depending on the method and solvent used, but is usually 0 to 120 ° C., preferably at 10 ° C. to 25 ° C. Although the reaction time varies depending on the reaction temperature, it is usually preferable to react within 30 minutes to 1 day, preferably within 2 hours.

[공정 E] 화학식(VII)로 표시되는 화합물의 제조[Step E] Preparation of Compound Represented by Formula (VII)

In order to obtain the compound represented by the general formula (VII), the compound represented by the general formula (IV) may be reacted with a halogen acetic acid alkyl ester or an alkyl halogen acetic acid alkyl ester in the presence of a base.

Halogen acetate alkyl esters or alkyl halogen acetate alkyl esters are readily available as known compounds, and those not available as alkyl halogen acetate alkyl esters can be obtained by bromination reactions to alkyl acetate alkyl esters. Halogen is a chlorine atom, a bromine atom. Iodine atoms.

As the solvent used in this process, N, N - dimethylformamide, N, N - dimethylacetamide, dimethyl sulfoxide, using a water-soluble single solvent such as acetonitrile, acetone, ethanol, methanol, or of 1 to 10% Use a solvent mixed with water. Among them, the most preferable solvent is acetone or dimethyl sulfoxide mixed with 1 to 5% water.

The base used is not particularly limited as long as it is a weak base or a strong base as long as it does not adversely affect the reaction. Alkali metal hydrides such as sodium hydride and lithium hydride, alkaline earth metal hydrides such as potassium hydride, sodium hydroxide and potassium hydroxide And alkali metal carbonates such as strong bases such as alkali metal hydroxides, lithium carbonate, potassium carbonate, potassium bicarbonate and cesium carbonate. As a base used, alkali metal carbonate is preferable and potassium carbonate is more preferable.

The reaction temperature is not particularly limited as long as the boiling point of the solvent used, but a relatively high temperature reaction is not preferable in order to suppress side reactions. Usually, it reacts at 0-90 degreeC. The reaction time varies depending on the reaction temperature, but usually 30 minutes to 1 day, preferably 30 to 120 minutes.

[공정 F-1] 화학식 (VIII)로 표시되는 화합물의 제조[Step F-1] Preparation of Compound Represented by Formula (VIII)

The compound represented by the formula (VIII) may be prepared from the compound of the formula (VII) by hydrolysis of a carboxylic acid ester in a water-soluble inorganic salt and alcohol solution, or the compound of formula (VII) and 2.0 M lithium hydroxide may be dissolved in THF and water. It reacts under the mixed solution to hydrolyze the ester.

As a solvent used in this process, an aqueous solvent mixed with water with alcohols such as methanol and ethanol is used.

As the base to be used, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like are used to form an aqueous solution of about 0.1 to 3 N depending on the form of the carboxylic acid alkali salt. A compound represented by the general formula (VIII) with an acid used for obtaining a carboxylic acid form is preferably used acetic acid, sodium bisulfate (NaHSO _4), or 0.1 ~ 3 N hydrochloric acid solution. In order to obtain the compound of formula (VIII) in carboxylic acid form, it is generally preferred to use 0.5 M NaHSO ₄ .

The reaction temperature is preferably reacted at a relatively low temperature in order to suppress side reactions, and usually at 0 ° C to room temperature. The reaction time varies depending on the reaction temperature, but usually 10 minutes to 3 hours, preferably 30 minutes to 1 hour. When 2.0 M lithium hydroxide is reacted under a mixture of THF and water, the reaction temperature is usually reacted at 0 ° C., and the reaction time is preferably reacted for 1 to 2 hours.

[공정 F-2] 화학식(VIII)로 표시되는 화합물의 제조[Step F-2] Preparation of Compound Represented by Formula (VIII)

The compound represented by the formula (VIII) is prepared from a compound of the formula (VII) by a salt substitution reaction of an allyl ester using a metal catalyst and an alkali metal salt or alkaline earth metal salt of 2-ethylhexanoate in an organic solvent.

As the solvent used in this step, anhydrous organic solvents such as chloroform, dichloromethane and ethyl acetate are used.

Tetrakis (triphenylphosphine) palladium (Pd (PPh ₃ ) ₄ ) is used as the metal catalyst to be used, and the amount of the metal catalyst to be used is preferably in the range of 0.01 equivalents to 0.1 equivalents.

The reaction temperature is preferably reacted at a relatively low temperature in order to suppress side reactions, and usually at 0 ° C to room temperature. The reaction time varies depending on the reaction temperature, but usually 10 minutes to 3 hours, preferably 30 minutes to 1 hour.

Compounds of these salts are separated purely by centrifugation or using ion exchange resins. The obtained compound of the metal salt form of formula (VIII) is easier to separate than the compound of the salt form prepared using Step F-1 (hydrolysis step).

[공정 G] 화학식(IV-B)로 표시되는 화합물의 제조 [Step G] Preparation of Compound Represented by Formula (IV-B)

The compound represented by the formula (IV-B) protects the phenol group with Grignard reagent without separating the compound represented by the formula (IV-A), and the alpha-hydrogen (α-) of thio or selenoether protons are treated with strong bases to produce nucleophiles, which are then reacted with various electrophilic compounds. This process will go through two stages of reaction in detail.

Below, a detailed process is demonstrated.

[Phenol Group Protection Reaction with Greennard Reagent]

[Alpha-hydrogen extraction and electrophilic compound addition reaction]

Nucleophiles are prepared by treating alpha-hydrogen (α-proton) of thio or selenoether with strong bases, followed by reaction of various electrophilic compounds.

[공정 H] 화학식(III-2)로 표시되는 화합물의 제조[Step H] Preparation of Compound Represented by Formula (III-2)

The compound represented by the formula (III-2) is sodium borohydride, a powerful reducing agent, by reducing the selenium metal under alcohol solvent conditions to form sodium hydrogen selenide, and then again under the strong acid and reflux conditions of hydrochloric acid and the like (III) It reacts with the aryl nitrile group represented by -1), and is a process of making selenocarboamide. As the solvent used in this process, alcohols such as methanol and ethanol and a small amount of pyridine are used. Sodium borohydride and selenium metal powder preferably use the same equivalents, and the hydrochloric acid used is 2-3 mol.

[공정 I] 화학식(III-3)로 표시되는 화합물의 제조[Step I] Preparation of Compound Represented by Formula (III-3)

The compound represented by formula (III-3) is obtained by reacting a compound of formula (III-2) with C1-C4 alkyl 2-chloroacetoacetate.

Examples of the solvent used in this step include alcohols such as methanol, ethanol, propanol and butanol and ethers such as ethyl ether, tetrahydrofuran and 1,4-dioxane. Among these, ethanol and tetrahydrofuran solvent are preferable.

The reaction temperature may vary depending on the solvent used, but is usually 25 to 150 ° C., preferably at 60 to 120 ° C. The reaction time may vary depending on the reaction temperature and the solvent used, but it is generally preferred to react within 6 hours to 1 day, preferably within 16 hours.

[공정 J] 화학식(III-4)로 표시되는 화합물의 제조[Step J] Preparation of Compound Represented by Formula (III-4)

The alcohol compound represented by the general formula (III-4) is obtained from the ester compound of the general formula (III-3) through a reduction reaction of the ester using a reducing agent.

Reducing agents used in the reduction reaction of the ester include hydrogenated aluminum reducing agents such as lithium aluminum hydride (LiAlH ₄ ), diisobutyl aluminum hydride (DIBAL-H), sodium borohydride, lithium borohydride and the like. Boron reducing agent reaction. Among them, a reaction using an aluminum hydride reducing agent is preferable, and lithium aluminum hydride (LiAlH ₄ ) and diisobutyl aluminum hydride (DIBAL-H) are most preferred.

Diethyl ether, tetrahydrofuran, dichloromethane, etc. are mentioned as anhydrous solvent used at this process, More preferably, dichloromethane.

The reaction temperature may vary depending on the solvent and reducing agent used, but is usually -100 to 60 ° C, preferably at -78 ° C to 25 ° C. The reaction time may vary depending on the reaction temperature and the solvent used, but it is generally preferred to react within 30 minutes to 6 hours, preferably within 2 hours.

[공정 K] 화학식(III)로 표시되는 화합물의 제조[Step K] Preparation of Compound Represented by Formula (III)

The compound represented by formula (III-A) is obtained through halogenation of an alcohol group from the compound of formula (III-4), and the compound represented by formula (III-B) is NaN from the compound of formula (III-4). Obtained using ₃ , wherein the compound represented by formula (III-C) is sulfonyl chloride substituted with alkyl or aryl in the hydroxy group of the compound of formula (III-4), preferably methanesulfonyl chloride or p -toluenesulfonyl Obtained by introducing chloride.

As the solvent used for the halogenation reaction, the methanesulfonyloxy group and the p -toluenesulfonyloxy gasification reaction, solvents such as N , N -dimethylformamide, diethyl ether, tetrahydrofuran, carbon tetrachloride, chloroform, dichloromethane and pyridine are used. do. Among them, the most preferred solvent is dichloromethane for the halogenation reaction, pyridine for the methanesulfonyloxy group and the p -toluenesulfonyloxy group reaction.

According to the halogen type, the halogenation reaction of alcohol is carried out with triphenylphosphine (TPP), N -chlorosuccinimide (NCS), triphenylphosphine, chlorine gas (Cl ₂ ), triphenylphosphine and The bromine atoms are triphenylphosphine and N -bromo, using carbon tetrachloride (CCl ₄ ), phosphorus pentachloride (PCl ₅ ), thionyl chloride (SOCl ₂ ), methanesulfonyl chloride (MeSO ₂ Cl), and the like. Succinimide (NBS), triphenylphosphine and bromine gas (BR3), triphenylphosphine and carbon tetrabromide (CBr ₄ ), phosphorus pentabromide (PBr ₅ ), thionyl bromide (SOBr ₂ ), and the like. The iodine atom is prepared using triphenylphosphine and N -iodine succinimide, triphenylphosphine and solid iodine, triphenylphosphine and carbon iodide (CI ₄ ), or the formula (IV). Sodium iodide (NaI) in acetone from chlorine or bromine compounds And halogen- prepared using iodine substitution method. Introduction of methanesulfonyloxy group, p -toluenesulfonyloxy group is prepared by reaction with methanesulfonylchloride or p -toluenesulfonylchloride in pyridine solvent. Double most preferred leaving group is a chlorine atom and a bromine atom, this is the most preferred of the preparation of triphenylphosphine and N-a production method using a bromosuccinimide-chloro-succinimide, N.

In this process, the reaction temperature may vary depending on the method or solvent used, but is usually -10 to 40 ° C, preferably 10 to 25 ° C. The reaction time may vary depending on the reaction temperature and the solvent used, but it is generally preferred to react within 30 minutes to 1 day, preferably within 2 hours.

[공정 L] 화학식(L-1, L-2)로 표시되는 화합물의 제조[Step L] Preparation of Compound Represented by Formulas (L-1, L-2)

After dissolving the compound represented by the formula (VII) prepared in step E in methylene chloride (CH2Cl2) and the reaction temperature is maintained at 0 ~ 5 ℃ 1 m-CPBA (m-chloroperbenzoic acid 1 equivalent) L-1 substance In addition, 2 equivalents of m-CPBA (m-chloroperbenzoic acid) can be used to prepare L-2 substances.

The Y compound of the formula (I) thus obtained is an important substance as a ligand of the PPAR protein. Moreover, this compound has chiral carbon, and its stereoisomer exists. The scope of the present invention includes the selenazole derivative compounds of formula I, their stereoisomers, solvates and salts thereof.

The selenazole derivative compound represented by the formula (I) according to the present invention or a pharmaceutically acceptable salt of the compound is useful as an activator composition of the Peroxysome Proliferator Activated Receptor (PPAR). In addition, the selenazole derivative compounds of formula (I), hydrates thereof, solvates thereof, stereoisomers thereof and pharmaceutically acceptable salts thereof according to the present invention may be activated by activating a Peroxysome Proliferator Activated Receptor (PPAR). For treating and preventing atherosclerosis, fatty liver or hyperlipidemia, for treating and preventing hypercholesterolemia, for treating and preventing diabetes, for treating and preventing obesity, for strengthening muscles, for improving endurance, for improving memory, for treating and preventing dementia or Parkinson's disease It is useful as a pharmaceutical composition, a functional food supplement, a functional beverage, a food additive, a functional cosmetic, and an animal feed composition. In addition, selenazole derivatives of formula (I), hydrates thereof, solvates thereof, stereoisomers thereof and pharmaceutically acceptable salts thereof according to the present invention are functional cosmetic compositions for preventing obesity and improving obesity, fatty liver, muscle strengthening and endurance. The functional cosmetic composition is useful as an ointment, or as a lotion or cream, to be applied to desired body parts before and after exercise, and can be used for a long time to achieve a desired effect. In addition, the selenazole derivatives of formula (I), hydrates thereof, solvates thereof, stereoisomers thereof and pharmaceutically acceptable salts thereof according to the present invention may be used to prevent or treat foot ulcers caused by diabetes mellitus called diabetes or diabetic ulcer. It may be formulated in an ointment form and applied to each part of the body.

The pharmaceutically acceptable salts may form salts with carboxylic acids of the selenazole derivatives of Formula I above and include all pharmaceutically acceptable organic salts such as dicyclohexylamine, N -methyl- D -glucamine As the inorganic salt, Li ⁺ , Na ⁺ , K ⁺ , Ca ²⁺ , Mg ^2+, etc. are preferable as the alkali metal and alkaline earth metal ions.

The amount of selenazole derivatives of formula (I), hydrates thereof, solvates thereof, stereoisomers thereof and pharmaceutically acceptable salts thereof, as well as specific compounds, methods of administration, the subjects to be treated, and the therapeutic agents used to achieve the therapeutic effect according to the invention It depends on the disease, but depends on the dosage of conventional medicine, more preferably the effective dosage of the compound of formula (I) is administered within the range of 1 to 100 mg / kg (weight) / day. In addition, within a daily effective dosage range is divided into once a day or several times a day. In addition, depending on the formulation, both oral or topical administrations are possible. Oral administration of the pharmaceutical composition according to the present invention can be prepared in any of a variety of existing forms, for example tablets, powders, dry syrups, chewable tablets, granules, chewing tablets, capsules, soft capsules, pills, It can exist in various forms, such as drink, sublingual tablet, and the like. Tablets according to the present invention may be administered to a patient in any form or manner in which an effective amount is bioavailable, ie, by oral route, depending on the nature of the disease state to be treated or prevented, the stage of the disease, and other relevant circumstances. Suitable dosage forms or modes can be readily selected and the compositions according to the invention may comprise one or more pharmaceutically acceptable excipients, wherein the proportions and properties of such excipients may depend upon the solubility and chemical properties of the selected tablet, It may be determined by the route of administration chosen and standard pharmaceutical practice.

Figure 1-Fatty liver treatment efficacy test results

[실시예]EXAMPLE

Hereinafter, the method of the present invention will be described in detail with reference to Examples. However, the present invention is not limited to these examples.

Preparation Example 1 Preparation of Compound III-2a

[Step H]

3.95 g (50 mmol) of selenium powder is added to 50 ml of ethanol under nitrogen conditions, and then 2.02 g (53 mmol) of sodium borohydride is added slowly and carefully for 30 minutes (hydrogen gas evolution). 11.9 g (70 mmol) of 4- (trifluoromethyl) benzonitrile and 8 ml of pyridine are added to the hydrogen selenide, and 25 ml of 2M hydrochloric acid is slowly added dropwise for 1 hour and a half while refluxing at 80 ° C. After stirring for 30 minutes, the precipitated target compound is filtered and washed with hexane and water. This was again recrystallized using a benzene solvent to give 15.1 g (yield: 91%) of the title compound III-2a as a pure yellow solid.

¹ H NMR (300 MHz, CDCl ₃ ) δ 11.07 (b, 1H), 10.43 (b, 1H), 7.99 (d, 2H, J = 8.5 Hz), 7.77 (d, 2H, J = 8.3 Hz)

Preparation Example 2 Preparation of Compound III-3a

[Process I]

2.52 g (10.0 mmol) of compound III-2a was dissolved in 35 ml of tetrahydrofuran at room temperature, and then 1.22 ml (10.0 mmol, 1.0 equivalent) of ethyl 2-chloroacetoacetate was slowly added for 20 minutes. After complete addition, the mixture was stirred for 30 minutes at room temperature, and the reaction was heated to reflux for 12 hours at 75 to 80 ° C. After completion of the reaction, the temperature was lowered to room temperature, and 20 ml of 50% aqueous sodium hydroxide solution was added thereto, followed by stirring for 20 minutes. Extract the organic layer using ethyl acetate and aqueous salt solution, and remove the moisture of the organic layer with magnesium sulfate. After filtration, the solution was distilled under reduced pressure to obtain 3.33 g (yield: 95%) of the title compound III-3a .

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.02 (d, 2H, J = 8.1 Hz), 7.69 (d, 2H, J = 8.2 Hz), 3.88 (s, 3H), 2.79 (s, 3H)

Preparation Example 3 Preparation of Compound III-4a

[Step J]

2.1 g (6.0 mmol) of ethyl ester compound III-3a obtained in Example 2 under nitrogen conditions are completely dissolved in 100 ml of anhydrous dichloromethane, and the reaction is then cooled sufficiently to -78 ° C. 16.6 mL (1.0 M -hexane solution, 2.5 equiv) of diisobutylaluminum hydride (DIBAL-H) is added slowly over 30 minutes. After reacting for 30 minutes at this temperature, the temperature is raised to -10 ° C for 30 minutes. After completion of the reaction, excess diisobutylaluminum hydride was terminated with ethyl acetate, extracted with 10% sulfuric acid and ethyl acetate, and water was removed with magnesium sulfate. After filtration using a short silica gel column, the solvent was distilled under reduced pressure to obtain 1.74 g (yield: 94%) of the title compound III-4a .

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.96 (d, 2H, J = 8.1 Hz), 7.65 (d, 2H, J = 8.2 Hz), 4.88 (d, 2H, J = 5.3 Hz), 2.45 (s , 3H)

Preparation Example 4 Preparation of Compound III-A-1

[Step K-1]

1.13 g (3.66 mmol) of the compound III-4a obtained in Example 3 are dissolved in 30 ml of anhydrous dichloromethane, and then 1.06 g (4.03 mmol, 1.1 equivalents) of triphenylphosphine (TPP) is completely dissolved. 717 mg (4.03 mmol, 1.1 equiv) of N -chloro succinimide are slowly added at room temperature. After further stirring for 1 hour, the solvent was distilled off under reduced pressure, and triphenylphosphinooxide was precipitated with hexane: ethyl acetate = 5: 1 solvent, and the resultant was filtered and distilled under reduced pressure to yield 1.07 g of the target compound III-A-1 (yield: 90 %) Was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.95 (d, 2H, J = 8.2 Hz), 7.66 (d, 2H, J = 8.3 Hz), 4.84 (s, 2H), 2.48 (s, 3H)

Preparation Example 5 Preparation of Compound III-B-1

[Step K-2]

352 mg (1.1 equivalents) of compound III-4a obtained in Preparation Example 3 was slowly dissolved in 5 ml of a CCl ₄ -DMF (1: 4) solvent, and then 508 mg (2.2 equivalents) of PPh3 and 78 mg (1.2 equivalents) of NaN ₃ were added dropwise. After slowly raising the temperature to 90 ℃ and the starting reagent disappears by TLC lower the temperature to 25 ℃. Lower to 25 ° C, stir for another 10 minutes, and terminate the reaction with 4 ml of distilled water. After extraction with ethyl ether, the temperature is lowered to 0 ℃ and the crystallization of Triphenylphosphine-oxide is carried out using a filter. The remaining reaction product was flash silica column to obtain 271 mg (yield: 85%) of the title compound III-B-1 (FABMS: 321 [M + H] ⁺ ).

Preparation Example 6 Preparation of Compound III-C-1

[Step K-3]

352 mg (1.1 equivalents) of compound III-4a obtained in Preparation Example 3 was dissolved in 5 ml of MC (methylene chloride) solvent and the temperature was lowered to 0 ° C. Then carefully add 190 mg (1.0 equiv) of para-toluenesulfonyl chloride (ρ-TsCl) and Et ₃ N (1.5 equiv) and continue stirring. After completion of the reaction, the layers were partitioned with distilled water and MC solvent and the organic layer was concentrated. Then, 431 mg (yield: 91%) of the title compound III-C-1 was obtained by flash silica column (FABMS: 476 [M + H] ⁺ ).

Example 1 Preparation of Compound S1

[Step A]

Under nitrogen conditions 468 mg (2 mmol) of 4-idodo-2-methylphenol are dissolved in 20 ml of anhydrous tetrahydrofuran and the temperature is kept at 0 ° C. 1.5 ml of isopropyl magnesium chloride (2M) is slowly added and reacted for 10 minutes. After sufficiently cooling the reaction solution to -78 ℃,tert-Butyl lithium 2.00 ml (1.7MHexane solution, 1.0 equiv) was added slowly. After further stirring for 10 minutes, 64 mg (2 mmol, 1.0 equiv) of solid sulfur (S) at the same temperature are added in one portion. After the reaction for 40 minutes until the temperature of the reactant is 15 ℃, the compound prepared in Preparation Example 4 at the same temperatureIII-A-1 652 mg (2 mmol, 1.0 equiv) is dissolved in 10 ml of dry THF and slowly added. After 1 hour of further reaction, the reaction was terminated with an aqueous solution of ammonium chloride. The organic solvent was extracted using ethyl acetate and an aqueous salt solution, and the organic layer was removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound. 705 mg (yield: 82%) were obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.91 (d, 2H, J = 8.1 Hz), 7.63 (d, 2H, J = 8.0 Hz), 7.21 (m, 1H), 7.12 (m, 1H), 6.67 (d, 2H, J = 8.2 Hz), 4.15 (s, 2H), 2.19 (s, 3H), 2.17 (s, 3H)

Example 2 Preparation of Compound S2

[Step A]

Under nitrogen conditions 468 mg (2 mmol) of 4-idodo-2-methylphenol are dissolved in 20 ml of anhydrous tetrahydrofuran and the temperature is kept at 0 ° C. 1.5 ml of isopropyl magnesium chloride (2M) is slowly added and reacted for 10 minutes. After the reaction solution was sufficiently cooled to −78 ° C., 2.00 mL of tert -butyllithium (1.7 M -hexane solution, 1.0 equivalent) was slowly added. After further stirring for 10 minutes, 158 mg (2 mmol, 1.0 equiv) of selenium (Se) in solid phase are added at a time at the same temperature. After 40 minutes of reaction until the temperature of the reactant reaches 15 ° C, 652 mg (2 mmol, 1.0 equivalent) of compound III-A-1 prepared in Preparation Example 4 was slowly added to 10 ml of dry THF at the same temperature. . After 1 hour of further reaction, the reaction was terminated with an aqueous solution of ammonium chloride. The organic solvent was extracted using ethyl acetate and an aqueous salt solution, and the organic layer was removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 773 mg (yield: 81%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.89 (d, 2H, J = 8.1 Hz), 7.63 (d, 2H, J = 8.2 Hz), 7.24 (m, 1H), 7.14 (m, 1H), 6.67 (d, 2H, J = 8.2 Hz), 4.17 (s, 2H), 2.18 (s, 3H), 2.13 (s, 3H)

Example 3 Preparation of Compound S3

[Process B]

860 mg (2 mmol) of compound S1 and 290 mg (2.0 equiv) of imidazole are completely dissolved in 20 ml of dimethylformamide. tert - butyldimethylsilyl chloride was added to 165 mg (1.1 equivalent) slowly and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the mixture was extracted using aqueous ammonium chloride solution and ethyl acetate, and water was removed from the organic layer using magnesium sulfate. After purification using a silica gel column, the solvent was distilled off under reduced pressure to obtain 1053 mg (yield: 95%) of the title compound. (FABMS: 558 [M + H] ⁺ )

Example 4 Preparation of Compound S4

[Process B]

954 mg (2 mmol) of compound S2 and 290 mg (2.0 equiv) of imidazole are completely dissolved in 20 ml of dimethylformamide. tert - butyldimethylsilyl chloride was added to 165 mg (1.1 equivalent) slowly and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the mixture was extracted using aqueous ammonium chloride solution and ethyl acetate, and water was removed from the organic layer using magnesium sulfate. After purification using a silica gel column, the solvent was distilled off under reduced pressure to obtain 1099 mg (yield: 93%) of the title compound. (FABMS: 606 [M + H] ⁺ )

Example 5 Preparation of Compound S5

[Process E]

430 mg (1 mmol) of compound S1 and 10 ml of acetone with 5% water and 346 mg (2.5 mmol, 2.5 equiv) of potassium carbonate are mixed well at room temperature. 134 µL (1.2 mmol, 1.2 equivalents) of ethyl bromoacetate is added and stirred vigorously for 4 hours. After completion of the reaction, the mixture was extracted using an aqueous salt solution and ethyl acetate, and water was removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography with hexane / ethyl acetate (v / v = 5: 1) solvent to obtain 480 mg (yield: 93%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.90 (d, 2H, J = 8.1 Hz), 7.64 (d, 2H, J = 8.2 Hz), 7.25 (m, 1H), 7.14 (m, 1H), 6.67 (d, 2H, J = 8.2 Hz), 4.61 (s, 2H), 4.23 (m, 2H), 4.16 (s, 2H), 2.24 (s, 3H), 2.21 (s, 3H), 1.28 (t, 3H, J = 3.7 Hz)

Example 6 Preparation of Compound S6

[Process E]

Mix 477 mg (1 mmol) of compound S2 with 10 ml of acetone with 5% water and 346 mg (2.5 mmol, 2.5 equiv) of potassium carbonate at room temperature. 134 µL (1.2 mmol, 1.2 equivalents) of ethyl bromoacetate is added and stirred vigorously for 4 hours. After completion of the reaction, the mixture was extracted using an aqueous salt solution and ethyl acetate, and water was removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography with hexane / ethyl acetate (v / v = 5: 1) solvent to obtain the title compound 523 mg (yield: 93%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.90 (d, 2H, J = 8.1 Hz), 7.64 (d, 2H, J = 8.2 Hz), 7.27 (m, 1H), 7.20 (m, 1H), 6.68 (d, 2H, J = 8.2 Hz), 4.61 (s, 2H), 4.23 (m, 2H), 4.19 (s, 2H), 2.23 (s, 3H), 2.15 (s, 3H), 1.27 (t, 3H, J = 3.7 Hz)

Example 7 Preparation of Compound S7

[Process E]

Mix 430 mg (1 mmol) of compound S1 with 10 ml of acetone with 5% water and 346 mg (2.5 mmol, 2.5 equiv) of potassium carbonate at room temperature. Add 210 µl (1.2 mmol, 1.2 equivalents) of ethyl-2-bromo-2-methylpropaneate, heat 60-90 ° C. with acetone, and stir vigorously for 4 hours. After completion of the reaction, the mixture was extracted using an aqueous salt solution and ethyl acetate, and water was removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography with hexane / ethyl acetate (v / v = 5: 1) solvent to obtain 326 mg (yield: 60%) of the title compound.

(FABMS: 558 [M + H] ⁺ ).

Example 8 Preparation of Compound S8

[Process E]

Mix 430 mg (1 mmol) of compound S1 with 10 ml of acetone with 5% water and 346 mg (2.5 mmol, 2.5 equiv) of potassium carbonate at room temperature. 146 μl (1.2 mmol, 1.2 equivalents) of ethyl-2-bromobutyrate is added and heated to 60 ° C. to 90 ° C. with acetone, and stirred vigorously for 4 hours. After completion of the reaction, the mixture was extracted using an aqueous salt solution and ethyl acetate, and water was removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography with hexane / ethyl acetate (v / v = 5: 1) solvent to obtain 451 mg (yield: 83%) of the title compound. (FABMS: 558 [M + H] ⁺ ).

Example 9 Preparation of Compound S9

[Process E]

Mix 430 mg (1 mmol) of compound S1 with 10 ml of acetone with 5% water and 346 mg (2.5 mmol, 2.5 equiv) of potassium carbonate at room temperature. Add 155 μl (1.2 mmol, 1.2 eq) of ethyl-2-bromo propionate, heat 60-90 ° C. with acetone, and stir vigorously for 4 hours. After completion of the reaction, the mixture was extracted using an aqueous salt solution and ethyl acetate, and water was removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography with hexane / ethyl acetate (v / v = 5: 1) solvent to obtain 429 mg (yield: 81%) of the title compound. (FABMS: 544 [M + H] ⁺ ).

Example 10 Preparation of Compound S10

[Process E]

478 mg (1 mmol) of compound S2 and 10 ml of acetone with 5% water, 346 mg (2.5 mmol, 2.5 equiv) of potassium carbonate are mixed well at room temperature. Add 210 μl of ethyl-2-bromo-2-methylpropaneate (1.2 mmol, 1.2 equiv), heat 60-90 ° C. with acetone, and stir vigorously for 4 hours. After completion of the reaction, the mixture was extracted using an aqueous salt solution and ethyl acetate, and water was removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography with hexane / ethyl acetate (v / v = 5: 1) solvent to obtain 349 mg (yield: 59%) of the title compound. (FABMS: 606 [M + H] ⁺ ).

Example 11 Preparation of Compound S11

[Process E]

Mix 478 mg (1 mmol) of compound S2 with 10 ml of acetone with 5% water and 346 mg (2.5 mmol, 2.5 equiv) of potassium carbonate at room temperature. 146 μl (1.2 mmol, 1.2 equivalents) of ethyl-2-bromobutyrate is added and heated to 60 ° C. to 90 ° C. with acetone, and stirred vigorously for 4 hours. After completion of the reaction, the mixture was extracted using an aqueous salt solution and ethyl acetate, and water was removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography with hexane / ethyl acetate (v / v = 5: 1) solvent to obtain 490 mg (yield: 83%) of the title compound. (FABMS: 606 [M + H] ⁺ ).

Example 12 Preparation of Compound S12

[Process E]

478 mg (1 mmol) of compound S2 and 10 ml of acetone with 5% water, 346 mg (2.5 mmol, 2.5 equiv) of potassium carbonate are mixed well at room temperature. Add 155 μl (1.2 mmol, 1.2 eq) of ethyl-2-bromo propionate, heat 60-90 ° C. with acetone, and stir vigorously for 4 hours. After completion of the reaction, the mixture was extracted using an aqueous salt solution and ethyl acetate, and water was removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography with hexane / ethyl acetate (v / v = 5: 1) solvent to obtain 462 mg (yield: 80%) of the title compound. (FABMS: 592 [M + H] ⁺ ).

Example 13 Preparation of Compound S13

[Step C]

544 mg (1 mmol) of compound S3 are dissolved in 10 mL of anhydrous tetrahydrofuran and the temperature is lowered to -78 ° C. 1.8 ml (1.8 M , 2.0 equiv) of lithium diisopropyl amide (LDA) was slowly added thereto. Then, 137 μl (1.0 mmol) of benzyl bromide was added to the reaction solution, and the reaction temperature was gradually raised to room temperature. After 30 minutes of further reaction, the reaction was terminated with an aqueous solution of ammonium chloride. The organic solvent was extracted using ethyl acetate and an aqueous salt solution, and the moisture of the organic layer was removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 526 mg (yield: 83%) of the title compound. (FABMS: 648 [M + H] ⁺ ).

Example 14 Preparation of Compound S14

[Step C]

591 mg (1 mmol) of compound S4 are dissolved in 10 mL of anhydrous tetrahydrofuran and the temperature is lowered to -78 ° C. 1.8 ml (1.8 M , 2.0 equiv) of lithium diisopropylamide (LDA) were slowly added thereto. Then, 137 μl (1.0 mmol) of benzyl bromide was added to the reaction solution, and the reaction temperature was gradually raised to room temperature. After 30 minutes of further reaction, the reaction was terminated with an aqueous solution of ammonium chloride. The organic solvent was extracted using ethyl acetate and an aqueous salt solution, and the moisture of the organic layer was removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 538 mg (yield: 79%) of the title compound. (FABMS: 694 [M + H] ⁺ ).

Example 15 Preparation of Compound S15

[Step C]

699 mg (1 mmol) of compound S3 are dissolved in 20 mL of anhydrous tetrahydrofuran and the temperature is lowered to -78 ° C. 1.8 ml (1.8 M , 2.0 equiv) of lithium diisopropylamide (LDA) was slowly added thereto. Thereafter, 270 µl (2.0 mmol) of 2-chloro-5-fluorobenzylbromide was added to the reaction solution, and the reaction temperature was gradually raised to room temperature. After 30 minutes of further reaction, the reaction was terminated with an aqueous solution of ammonium chloride. The organic solvent was extracted using ethyl acetate and an aqueous salt solution, and the moisture of the organic layer was removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 531 mg (yield: 76%) of the title compound. (FABMS: 700 [M + H] ⁺ ).

Example 16 Preparation of Compound S16

[Step C]

746 mg (1 mmol) of compound S4 are dissolved in 20 mL of anhydrous tetrahydrofuran and the temperature is lowered to -78 ° C. 1.8 ml (1.8 M , 2.0 equiv) of lithium diisopropylamide (LDA) was slowly added thereto. Thereafter, 270 µl (2.0 mmol) of 2-chloro-5-fluorobenzylbromide was added to the reaction solution, and the reaction temperature was gradually raised to room temperature. After 30 minutes of further reaction, the reaction was terminated with an aqueous solution of ammonium chloride. The organic solvent was extracted using ethyl acetate and an aqueous salt solution, and the moisture of the organic layer was removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 552 mg (yield: 74%) of the title compound. (FABMS: 746 [M + H] ⁺ ).

Example 17 Preparation of Compound S17

[Step C]

700 mg (1 mmol) of compound S3 are dissolved in 20 mL of anhydrous tetrahydrofuran and the temperature is lowered to -78 ° C. 1.8 ml (1.8 M , 2.0 equiv) of lithium diisopropylamide (LDA) was slowly added thereto. Thereafter, 282 µl (2.0 mmol) of 3,4,5-trifluorobenzylbromide was added to the reaction solution, and the reaction temperature was gradually raised to room temperature. After 30 minutes of further reaction, the reaction was terminated with an aqueous solution of ammonium chloride. The organic solvent was extracted using ethyl acetate and an aqueous salt solution, and the moisture of the organic layer was removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 525 mg (yield: 75%) of the title compound. (FABMS: 702 [M + H] ⁺ ).

Example 18 Preparation of Compound S18

[Step C]

747 mg (1 mmol) of compound S4 are dissolved in 20 mL of anhydrous tetrahydrofuran and the temperature is lowered to -78 ° C. 1.8 ml (1.8 M , 2.0 equiv) of lithium diisopropylamide (LDA) was slowly added thereto. Thereafter, 282 µl (2.0 mmol) of 3,4,5-trifluorobenzylbromide was added to the reaction solution, and the reaction temperature was gradually raised to room temperature. After 30 minutes of further reaction, the reaction was terminated with an aqueous solution of ammonium chloride. The organic solvent was extracted using ethyl acetate and an aqueous salt solution, and the moisture of the organic layer was removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 523 mg (yield: 70%) of the title compound. (FABMS: 750 [M + H] ⁺ ).

Example 19 Preparation of Compound S19

[Step C]

682 mg (1 mmol) of compound S3 are dissolved in 20 mL of anhydrous tetrahydrofuran and the temperature is lowered to -78 ° C. 1.8 ml (1.8 M , 2.0 equivalents) of lithium diisopropylamide (LDA) was slowly added thereto. Thereafter, 259 μl (2.0 mmol) of 2,5-difluorobenzylbromide was added to the reaction solution, and the reaction temperature was gradually raised to room temperature. After 30 minutes of further reaction, the reaction was terminated with an aqueous solution of ammonium chloride. The organic solvent was extracted using ethyl acetate and an aqueous salt solution, and the moisture of the organic layer was removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 518 mg (yield: 76%) of the title compound. (FABMS: 684 [M + H] ⁺ ).

Example 20 Preparation of Compound S20

[Step C]

724 mg (1 mmol) of compound S4 are dissolved in 20 mL of anhydrous tetrahydrofuran and the temperature is lowered to -78 ° C. 1.8 ml (1.8 M , 2.0 equivalents) of lithium diisopropylamide (LDA) was slowly added thereto. Thereafter, 259 μl (2.0 mmol) of 2,5-difluorobenzylbromide was added to the reaction solution, and the reaction temperature was gradually raised to room temperature. After 30 minutes of further reaction, the reaction was terminated with an aqueous solution of ammonium chloride. The organic solvent was extracted using ethyl acetate and an aqueous salt solution, and the moisture of the organic layer was removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 514 mg (yield: 71%) of the title compound. (FABMS: 732 [M + H] ⁺ ).

Example 21 Preparation of Compound S21

[Step C]

715 mg (1 mmol) of compound S3 are dissolved in 20 mL of anhydrous tetrahydrofuran and the temperature is lowered to -78 ° C. 1.8 ml (1.8 M , 2.0 equiv) of lithium diisopropylamide (LDA) was slowly added thereto. Thereafter, 300 µl (2.0 mmol) of 2,5-dichlorobenzyl bromide was added to the reaction solution, and the reaction temperature was gradually raised to room temperature. After 30 minutes of further reaction, the reaction was terminated with an aqueous solution of ammonium chloride. The organic solvent was extracted using ethyl acetate and an aqueous salt solution, and the moisture of the organic layer was removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 529 mg (yield: 74%) of the title compound. (FABMS: 716 [M + H] ⁺ ).

Example 22 Preparation of Compound S22

[Step C]

762 mg (1 mmol) of compound S4 are dissolved in 20 mL of anhydrous tetrahydrofuran and the temperature is lowered to -78 ° C. 1.8 ml (1.8 M , 2.0 equiv) of lithium diisopropylamide (LDA) was slowly added thereto. Thereafter, 300 µl (2.0 mmol) of 2,5-dichlorobenzyl bromide was added to the reaction solution, and the reaction temperature was gradually raised to room temperature. After 30 minutes of further reaction, the reaction was terminated with an aqueous solution of ammonium chloride. The organic solvent was extracted using ethyl acetate and an aqueous salt solution, and the moisture of the organic layer was removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 541 mg (yield: 71%) of the title compound. (FABMS: 762 [M + H] ⁺ ).

Example 23 Preparation of Compound S23

[Step C]

732 mg (1 mmol) of compound S3 are dissolved in 20 mL of anhydrous tetrahydrofuran and the temperature is lowered to -78 ° C. 1.8 ml (1.8 M , 2.0 equiv) of lithium diisopropylamide (LDA) was slowly added thereto. Thereafter, 514 mg (2.0 mmol) of 2-fluoro-5-trifluoromethyl benzyl bromide was added to the reaction solution, and the reaction temperature was gradually raised to room temperature. After 30 minutes of further reaction, the reaction was terminated with an aqueous solution of ammonium chloride. The organic solvent was extracted using ethyl acetate and an aqueous salt solution, and the moisture of the organic layer was removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 534 mg (yield: 73%) of the title compound (FABMS: 734 [M + H] ⁺ ).

Example 24 Preparation of Compound S24

[Step C]

779 mg (1 mmol) of compound S4 are dissolved in 20 mL of anhydrous tetrahydrofuran and the temperature is lowered to -78 ° C. 1.8 ml (1.8 M , 2.0 equiv) of lithium diisopropylamide (LDA) was slowly added thereto. Then, 514 mg (2.0 mmol) of 2-fluoro-5-trifluoromethyl benzylbromide was added to the reaction solution, and the reaction temperature was gradually raised to room temperature. After 30 minutes of further reaction, the reaction was terminated with an aqueous solution of ammonium chloride. The organic solvent was extracted using ethyl acetate and an aqueous salt solution, and the moisture of the organic layer was removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 545 mg (yield: 70%) of the title compound (FABMS: 782 [M + H] ⁺ ).

Example 25 Preparation of Compound S25

[Process G]

430 mg (1 mmol) of compound S1 are dissolved in 10 ml of anhydrous tetrahydrofuran under nitrogen conditions, and the temperature is maintained at 0 ° C. 1 ml of isopropylmagnesium chloride (2M) is slowly added and reacted for 10 minutes. After sufficiently cooling the reaction solution to −78 ° C., 1.8 ml (1.8 M , 2.0 equivalents) of lithium diisopropylamide (LDA) was slowly added thereto. Then, 137 μl (1.0 mmol) of benzyl bromide was added to the reaction solution, and the reaction temperature was gradually raised to room temperature. After 30 minutes of further reaction, the reaction was terminated with an aqueous solution of ammonium chloride. The organic solvent was extracted using ethyl acetate and an aqueous salt solution, and the moisture of the organic layer was removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 426 mg (yield: 80%) of the title compound. (FABMS: 534 [M + H] ⁺ ).

Example 26 Preparation of Compound S26

[Process G]

Under nitrogen conditions 478 mg (1 mmol) of compound S2 are dissolved in 10 ml of anhydrous tetrahydrofuran and the temperature is maintained at 0 ° C. 1 ml of isopropylmagnesium chloride (2M) is slowly added and reacted for 10 minutes. After sufficiently cooling the reaction solution to −78 ° C., 1.8 ml (1.8 M , 2.0 equivalents) of lithium diisopropylamide (LDA) was slowly added thereto. Then, 137 μl (1.0 mmol) of benzyl bromide was added to the reaction solution, and the reaction temperature was gradually raised to room temperature. After 30 minutes of further reaction, the reaction was terminated with an aqueous solution of ammonium chloride. The organic solvent was extracted using ethyl acetate and an aqueous salt solution, and the moisture of the organic layer was removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 457 mg (yield: 78%) of the title compound. (FABMS: 582 [M + H] ⁺ ).

[Examples 27-36]

Compounds S27 to S46 of Table 1 were prepared using the method of Examples 25 and 26, and MS of the prepared compound was shown.

TABLE 1

Example 47 Preparation of Compound S47

[Step D]

646 mg (1 mmol) of Compound S13 are dissolved completely in 10 ml of tetrahydrofuran. Slowly add 2.5 mL (1 M -tetrahydrofuran solution, 2.5 equiv) of tetrabutylammonium fluoride (TBAF) at room temperature. After 30 minutes of reaction, the mixture was extracted using aqueous ammonium chloride solution and ethyl acetate, and the organic layer was removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 479 mg (yield: 92%) of the title compound. (FABMS: 534 [M + H] ⁺ ).

Example 48 Preparation of Compound S48

[Step D]

693 mg (1 mmol) of compound S14 are dissolved completely in 10 ml of tetrahydrofuran. Slowly add 2.5 mL (1 M -tetrahydrofuran solution, 2.5 equiv) of tetrabutylammonium fluoride (TBAF) at room temperature. After 30 minutes of reaction, the mixture was extracted using aqueous ammonium chloride solution and ethyl acetate, and the organic layer was removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 521 mg (yield: 90%) of the title compound. (FABMS: 582 [M + H] ⁺ ).

Examples 27 to 46 can be prepared using the method of Examples 47 to 48.

Example 49 Preparation of Compound S49

[Process E]

532 mg (1 mmol) of compound S25 and 10 ml of acetone with 5% water and 346 mg (2.5 mmol, 2.5 equiv) of potassium carbonate are mixed well at room temperature. 134 µL (1.2 mmol, 1.2 equivalents) of ethyl bromoacetate is added and stirred vigorously for 4 hours. After completion of the reaction, the mixture was extracted using an aqueous salt solution and ethyl acetate, and water was removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography with hexane / ethyl acetate (v / v = 5: 1) solvent to obtain 575 mg (yield: 93%) of the title compound. (FABMS: 620 [M + H] ⁺ ).

Example 50 Preparation of Compound S50

[Process E]

Mix 579 mg (1 mmol) of compound S26 with 10 ml of acetone with 5% water and 346 mg (2.5 mmol, 2.5 equiv) of potassium carbonate at room temperature. 134 µL (1.2 mmol, 1.2 equivalents) of ethyl bromoacetate is added and stirred vigorously for 4 hours. After completion of the reaction, the mixture was extracted using an aqueous salt solution and ethyl acetate, and water was removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography with hexane / ethyl acetate (v / v = 5: 1) solvent to obtain 605 mg (yield: 91%) of the title compound. (FABMS: 668 [M + H] ⁺ ).

[Examples 51 to 136]

Compounds S51 to S136 of Table 2 were prepared using the method of Examples 49 to 50, and the MS of the prepared compound was shown.

TABLE 2

Example 137 Preparation of Compound S137

[Process F]

618 mg (1 mmol) of compound S49 are mixed well with 15 ml of THF and 10 ml of water, and then 0.6 ml of a 2.0 M aqueous lithium hydroxide solution is slowly added at 0 ° C. After 60 minutes of stirring at 0 ° C., when the reaction was completed, 2.5 ml of 0.5 M NaHSO ₄ was added thereto, followed by extraction using an aqueous salt solution and ethyl acetate. After filtration, the solvent was distilled off under reduced pressure and purified by LH-20 column chromatography. 566 mg (yield 96%) of the title compound were obtained. (FABMS: 592 [M + H] ⁺ )

Example 138 Preparation of Compound S138

[Process F]

665 mg (1 mmol) of Compound S50 are mixed well with 15 ml of THF and 10 ml of water, and then 0.6 ml of a 2.0 M aqueous lithium hydroxide solution is slowly added at 0 ° C. After 60 minutes of stirring at 0 ° C., when the reaction was completed, 2.5 ml of 0.5 M NaHSO ₄ was added thereto, followed by extraction using an aqueous salt solution and ethyl acetate. After filtration, the solvent was distilled off under reduced pressure and purified by LH-20 column chromatography. 605 mg (yield 95%) of the title compound were obtained. (FABMS: 640 [M + H] ⁺ )

Examples 139 to 288

Compounds S139 to S288 of Table 3 were prepared using the method of Examples 87 to 88, and the MS of the prepared compound was shown.

TABLE 3

Example 289 Preparation of Compound S289

After dissolving 500 mg (1 mmol) of compound S185 in 10 ml of acetonitrile solvent, the reaction was continued for 20 minutes with careful dropwise addition of 181 mg (1 mmol) of dicyclohexylamine. After 8 ml of distilled water was added and the reaction was continued for 10 minutes, the solvent was lyophilized to obtain 674 mg (yield: 99%) of the title compound. (FABMS: 683 [M + H] ⁺ )

Example 290 Preparation of Compound S290

590 mg (1 mmol) of compound S186 is dissolved in 10 ml of acetonitrile solvent, and the reaction is continued for about 20 minutes with careful dropwise addition of 181 mg (1 mmol) of dicyclohexylamine. After 8 ml of distilled water was added and the reaction was continued for 10 minutes, the solvent was lyophilized to obtain 768 mg (yield: 99%) of the title compound. (FABMS: 731 [M + H] ⁺ )

Example 291 Preparation of Compound S291

[Process L]

Under nitrogen condition, 0.7 ml of anhydrous DMF was added to 10 mg (0.05 mmol, 5 mol%) of CuI, 845 mg (2.6 equiv) of CsCO3, and 234 mg (1 mmol) of 4-idodo-2-methylphenol to prevent air passage Seal with Teflon tape and fill with nitrogen. Then, 2-isobutyrylcyclohexanon (2-Isobutyrylcyclohexanon, 34 mg, 0.2 mmol, 20 mol%) used as a ligand and 320 mg (1 equivalent) of the amine compound III-B-1 prepared in Preparation Example 5 were added thereto. Carefully stir at room temperature for 8 hours. The reaction mass was neutralized with 10% HCl solution to pH 4, the organic layer was concentrated, and silica column was used to obtain 355 mg (yield: 79%) of the title compound (FABMS: 427 [M + H] ⁺ ).

Example 292 Preparation of Compound S292

[Process E-Process F]

Compound S291 subjected to 425 mg (1 eq) using the procedure of Example 39 and Example 87 The title compound 348mg (Yield 82%) (FABMS: 485 [M + H ] +).

Example 293 Preparation of Compound S293

[Process M]

474 mg (1 equivalent) of Tosyl Compound III-C-1 prepared in Preparation Example 6 was dissolved in 5 ml of acetonitrile solvent and 0.5 ml of DMF, followed by 490 mg (1.5 equivalents) of CsCO3.

Slowly add (ethyl 2- (4-hydroxy-3-methylphenoxy) acetate, 210 mg, 1 equiv) and stir at room temperature for 4 hours. TLC confirms that the Tosyl compound disappears and then terminates the reaction. The organic layer was purified by silica column to give 435 mg (yield: 85%) of the title compound (FABMS: 514 [M + H] ⁺ ).

Example 294 Preparation of Compound S294

[Process F]

Compound S293 ester compound 510 mg (1 equiv) were obtained using the process of Example 87 to yield 454 mg (yield: 94%) of the title compound (FABMS: 486 [M + H] ⁺ ).

Example 295 Preparation of Compound S295

Dissolve compound S5 (530 mg, 1 mmol) in CH2Cl2 (10 mL) and add m-CPBA (m-chloroperbenzoic acid, 170 mg, 1 mmol). The reaction mixture is kept at 0-5 ° C. The reaction is continued for about 1 hour under this temperature condition. After the reaction was terminated (confirmed by TLC), the mixture was separated by column chromatography using silica gel to obtain a compound S295 of cloudy yellow oil (485 mg, 89%). (FABMS: 546 [M + H] ⁺ ).

Example 296 Preparation of Compound S296

Dissolve compound S5 (530 mg, 1 mmol) in CH2Cl2 (10 mL) and add m-CPBA (m-chloroperbenzoic acid, 340 mg, 2 mmol). The reaction mixture is kept at 0-5 ° C. The reaction is continued for about 2 hours under this temperature condition. After the reaction was terminated (confirmed by TLC), the mixture was separated by column chromatography using silica gel to give a white solid compound S296 (516 mg, 92%). (FABMS: 562 [M + H] ⁺ ).

Example 297 Preparation of Compound S297

[Process F]

545 mg (1 equiv) of Compound S295 ester compound were obtained using the process of Example 87 to yield 476 mg (yield: 92%) of the title compound (FABMS: 518 [M + H] ⁺ ).

Example 298 Preparation of Compound S298

561 mg (1 equiv) of Compound S296 ester compound were obtained using the process of Example 87 to yield 490 mg (yield: 92%) of the title compound (FABMS: 534 [M + H] ⁺ ).

[시험예 1] 활성 및 독성 시험Test Example 1 Activity and Toxicity Test

We confirmed the PPARδ activity of the compound of formula I according to the present invention through a transfection assay, additionally selectivity of PPARα and PPARγ, a subtype of PPARs, and toxicity and animal experiments through MTT assay. In vivo activity verification was performed.

[Transfection assay][Transfection assay]

The assay was performed using CV-1 cells, and the cell culture was performed in a 37-well incubator containing 5% carbon dioxide in 96 wells using DMEM medium containing 10% FBS, DBS (delipidated) and 1% penicillin / streptomycin. It was performed on the plate. The experiment was performed in four stages: cell inoculation, transfection, developmental material treatment, and result confirmation. CV-1 cells were seeded at 5,000 cell / well in 96 well plates and transfected after 24 hours. β-galactosidase DNA, which provides full-length PPARs plasmid DNA and luciferase activity to report PPARs activity and transfection efficiency information, was performed using a Transfection Reagent. The developed material was dissolved in dimethyl sulfoxide (DMSO) and treated with various concentrations of cells using media. After incubation for 24 hours, cells were lysed using lysis buffer and luciferase and β-galactosidase activities were measured using a luminometer and a microplate reader. The measured luciferase value was corrected using the β-galactosidase value, and a graph was used to calculate the EC ₅₀ value.

Table 4 EC ₅₀ Data

As can be seen in Table 4 above, the compounds according to the invention are highly selective for PPARδ.

Compounds according to the invention exhibited an activity between 0.66 nM-300 nM against PPARδ.

[MTT assay][MTT assay]

Toxicity test for the compound of formula (I) according to the present invention was carried out using MTT assay. MTT is a yellow substance that dissolves in water, but when it enters living cells, it is transformed into purple crystals that do not dissolve in water by dehydrogenase in mitochondria. After dissolving this material in dimethyl sulfoxide, absorbance at 550 nm can be confirmed for cytotoxicity. The experimental method is as follows.

CV-1 cells were first seeded at 5,000 cell / well in 96 well plates. After incubation in a humidified 37 ° C. incubator containing 5% carbon dioxide for 24 hours, the compound ( S185 ) made by the present invention is added to CV-1 cells incubated at various concentrations. Incubated again for 24 hours, MTT reagent was added. After incubation for about 15 minutes, the resulting purple crystals were dissolved in dimethyl sulfoxide, and then absorbance was measured using a microplate reader, from which cytotoxicity was confirmed.

Experimental results showed that the compound of Formula I was not toxic at concentrations of 100-1000 times higher than the EC ₅₀ concentration for PPAR.

[동물실험][Animal Experiment]

[비만억제효과 검증][Verify the effects of obesity]

In order to assay the in vivo effect on the material according to the present invention, experiments using a mouse were performed. Mouse was used 8-week-old C57BL / 6 (SLC Co.), and a diet containing 35% fat to induce obesity. Carbohydrate, S185, S186 (10mg / Kg / day) were administered orally with high fat intake for 60 days. As a result, the S185 group gained only 39% of the body weight compared to the vehicle group, and the S186 group increased 42%.

[동맥경화억제효과 검증][Verification of Arteriosclerosis Inhibition Effect]

In vivo animal experiments were performed using ApoE-/-and Ldlr-/-mice, which are animal models of arteriosclerosis, to verify the effects of the atherosclerosis on the developmental material. The high-fat cholesterol diet (20% fat, 1.25% cholesterol; AIN-93G diet) was ingested orally at a concentration of 2 mg / Kg / day. After 28 days, whole-area plaque staining was performed using Sudan IV, and the effects of atherosclerosis inhibition were analyzed by comparison with the control group. As a result, in the case of ApoE-/-mouse administered S185 according to the present invention, the effect of inhibiting arteriosclerosis was confirmed by 60% compared to the control group, and in the case of Ldlr-/-mouse administered S185 according to the present invention, 36% The inhibitory effect of was observed.

[당뇨개선효과 검증][Verification of Diabetes Improvement Effect]

GTT (Glucose Tolerance Test) was conducted to verify the effect of improving diabetes on the substance according to the present invention. Glucose (1.5g / Kg) was intraperitoneally administered to mice administered orally for 57 days. Fasting blood glucose levels were lower in the groups receiving S185 and S186 (10 mg / Kg / day) than the control group. In addition, the blood glucose was rapidly decreased between 20 and 40 minutes in the group treated with the inventive substance, and glucose clearance completely occurred after 100 minutes. However, the group of mice receiving vehicle did not maintain normal blood glucose after 120 minutes. From these results , it was confirmed that the development materials S185 and S186 were all effective in improving diabetes.

[근 지구력 강화 및 근 기능 증진효과 검증][Verification of muscle endurance and muscle function enhancement effect]

Animal experiments were performed to verify the effects of strengthening muscle endurance and muscle function on the material according to the present invention. Since most of the production of muscle occurs in the developmental stage, pregnant rats were orally administered with the concentrations of S185 and S186 (10mg / Kg / day) during pregnancy, lactation, or gestation and lactation. There was no difference in weight and growth rate between the control group and the fetus. The muscles were observed after skin removal, and the treatment group was found to be redder than the control group. ATPase staining and immunostaining results also showed an increase in Type I muscle fibers in the treated group. To determine the effect of these changes on muscle endurance and muscle function, an experiment using a Treadmill was performed. As a result, the running time of the treatment group was significantly increased compared to the control group.

[Table 5] Muscle endurance test results

In addition, the effects of strengthening muscle endurance and muscle function have been demonstrated even when the developing substance is administered to adults. 10-week-old C57BL / 6 rats were exercised with oral administration of developmental materials S185 and S186 at a concentration of 10 mg / Kg. Exercise was performed using a Treadmill for 30 minutes, once a day for 30 days. Exercise conditions were exercised for 5 minutes at 2 meter / min, 5 minutes at 5 meter / min, 5 minutes at 8 meter / min, and 5 minutes at 20 meter / min. At the end of the experiment, Treadmill was used to test muscle endurance and muscle function. As a result, both the exercise time and the exercise distance of the treatment group increased compared to the control group.

[기억력 증진 실험][Memory enhancement experiment]

Animal experiments were performed to verify the treatment of dementia and Parkinson's disease by enhancing memory for the material according to the invention (adult C57BL / 6 at 8 weeks of age). Animal models of brain disease were made by injecting LPS into the brain prior to the experiment. Experiments were conducted in four groups divided by the developmental substance administration and exercise. The exercise conditions were 5 minutes at 2 meters / min, 5 minutes at 5 meters / min, 5 minutes at 8 meters / min, and 20 meters. Exercise was performed for 5 minutes at the rate / min. The Morris water maze test was performed after the end of the experiment. The results are summarized in the table below. The developmental materials and exercise proved the effect of treating dementia and Parkinson's disease through memory enhancement in brain disease models.

Table 6 Test Results

[지방간 치료효능 검증 실험][Test of efficacy of fatty liver treatment]

Animal experiments were performed to verify the effects of fatty liver treatment on the substances according to the invention (8-week-old adult C57BL / 6). Feeds containing 35% fat were used to induce fatty liver. Developmental substance S185 was orally administered once a day at a concentration of 10 mg / kg with high fat intake for 78 days. After the end of the experiment, liver tissue was extracted and fixed with paraformaldehyde solution, and then hematoxylin & eosin staining was performed. The results are shown in Figure 1, through which it was proved that the development material has an inhibitory effect on the development of fatty liver by high fat feed.

As described above, the novel compounds according to the present invention are characterized as PPAR activating ligands for the treatment and prevention of fatty liver, arteriosclerosis or hyperlipidemia, for the treatment and prevention of hypercholesterolemia, for the treatment and prevention of diabetes, the treatment and prevention of obesity As a pharmaceutical composition for the treatment, prevention of muscle diseases, treatment and prevention of muscle diseases, enhancement of endurance, memory enhancement, treatment and prevention of dementia or Parkinson's disease, functional food supplements, functional drinks, food additives, functional cosmetics and animal feed compositions It is a very likely compound to be used.

Claims

Selenazole derivatives of formula (I), hydrates thereof, solvates thereof, stereoisomers thereof or pharmaceutically acceptable salts thereof.

[Formula I]

[In Formula I, A is O, NR, S, S (= 0), S (= 0) 2 or Se;

B is hydrogen or
Is;

R 1 is hydrogen, C 1 -C 8 alkyl or halogen;

R 2 is hydrogen, C 1 -C 8 alkyl,
or
ego;

X a and X b are independently of each other CR or N;

R is hydrogen or C1-C8 alkyl;

R 3 is hydrogen, C 1 -C 8 alkyl or halogen;

R 4 and R 5 are independently of each other hydrogen, halogen or C1-C8 alkyl;

R 6 is hydrogen, halogen, C 1 -C 8 alkyl, C 2 -C 7 alkenyl, allyl, alkali metal, alkaline earth metal or a pharmaceutically acceptable organic salt;

R 21 , R 22 , and R 23 are each selected from C3-C12 containing one or more heteroatoms selected from hydrogen, halogen, CN, NO 2 , alkyl of C1-C7, aryl of C6-C12, N, O and S. Heteroaryl, 5- or 7-membered heterocycloalkyl, or C1-C7 alkoxy group;

m is an integer from 1-4;

p is an integer from 1-5;

s is an integer from 1-5;

u is an integer of 1-3;

w is an integer from 1-4;

The alkyl and alkoxy of R 1 , R 3 , R 4 , R 5 , R 6 , R 21 , R 22 and R 23 may be further substituted with one or more halogen, cycloalkyl of C 3 -C 7 or alkylamine of C 1 -C 5. Can be]
The method of claim 1,

R 1 is hydrogen, C 1 -C 5 alkyl or fluorine substituted with one or more fluorine; R 2 is hydrogen, C 1 -C 8 alkyl,
or
ego; X a and X b are independently of each other CR or N; R is hydrogen or C1-C8 alkyl; R 3 is hydrogen, C 1 -C 5 alkyl or halogen substituted or unsubstituted; R 4 and R 5 are, independently from each other, hydrogen, C1-C5 alkyl, optionally substituted with halogen; R 6 is hydrogen, alkyl of C1-C8, halogen, allyl, alkenyl of C2-C7, pharmaceutically acceptable organic salt, alkali metal or alkaline earth metal; R 21 , R 22 and R 23 independently of one another are hydrogen, halogen, CN, NO 2 , at least one selected from alkyl substituted or unsubstituted C 1 -C 7 alkyl, C 6 -C 12 aryl, N, O and S Selenazole derivatives, hydrates thereof, solvates thereof, characterized in that a C3-C12 heteroaryl containing a hetero atom, a 5-7 membered heterocycloalkyl or a halogen is a substituted or unsubstituted C1-C5 alkoxy group Stereoisomers thereof and pharmaceutically acceptable salts thereof.
The method of claim 1,

Selenazole derivatives of formula IV, hydrates thereof, solvates thereof, stereoisomers thereof and pharmaceutically acceptable salts thereof.

[Formula IV]

[Wherein A is O, NR, S or Se; R 1 , R 2 , R 3 , m and p are the same as defined in formula I of claim 1.]
The method of claim 1,

Selenazole derivatives of formula (VII), hydrates thereof, solvates thereof, stereoisomers thereof and pharmaceutically acceptable salts thereof.

[Formula VII]

[Wherein A, R 1 , R 2 , R 3 , R 4 , R 5 , m and p are the same as defined in formula (I) of claim 1; R 6a is C 1 -C 8 alkyl or allyl.]
The method of claim 1,

Selenazole derivatives of formula (VIII), hydrates thereof, solvates thereof, stereoisomers thereof and pharmaceutically acceptable salts thereof.

[Formula VIII]

[Wherein A, R 1 , R 2 , R 3 , R 4 , R 5 , m and p are the same as defined in formula I of claim 1, R 6b is a hydrogen atom or an alkali metal, an alkaline earth metal or a pharmaceutical Organic salts are acceptable.]
a) reacting a compound of Formula II with a Grignard reagent followed by reaction with an organolithium compound; And

b) adding sulfur (S) or selenium (Se) powder following step a);

c) reacting with a compound of formula III in succession to step b) to produce a compound of formula IV;

Method for producing a selenazole derivative of formula (I) according to claim 1 characterized in that it comprises a.

[Formula II]

[Formula III]

[Formula IV]

[Wherein A is O, NR, S or Se; R 1 , R 2 , R 3 , m and p are the same as defined in formula I of claim 1; X 1 is a bromine or iodine atom; X 2 is a leaving group that is highly reactive to chlorine, bromine, iodine or nucleophilic substitution.]
a) reacting a compound of Formula II with a Grignard reagent followed by reaction with an organolithium compound;

b) adding sulfur (S) or selenium (Se) powder following step a);

c) reacting with a compound of Formula III-A following step b) to produce a compound of Formula IV-A; And

d) protecting the phenol group of formula IV-A with an alkylsilyl group, followed by strong base treatment of alpha-hydrogen of a thio or seleno ether compound, adding a compound of formula VI and then deprotecting to prepare a compound of formula IV-B Doing;

Method for producing a selenazole derivative of formula (I) according to claim 1 characterized in that it comprises a.

[Formula II]

[Formula III-A]

[Formula IV-A]

[Formula VI]

[Formula IV-B]

[Wherein A is O, NR, S or Se; R 2 is
or
ego; R 1 , R 3 , R 21 , R 22, R 23 , X a , X b , R, m, p, s, u and w are the same as defined in formula (I) of claim 1; X 1 is a bromine or iodine atom; X 2 and X 3 are chlorine, bromine, iodine or leaving group.]
A compound of formula IV-A is reacted with a Grignard reagent, followed by treatment of alpha-hydrogen of a thio or seleno ether compound with a strong base, followed by reaction with a compound of formula VI to give a compound of formula IV-B. A process for preparing a selenazole derivative of formula (I) according to claim 1 characterized in that the preparation.

[Formula IV-A]

[Formula VI]

[Formula IV-B]

[Wherein A is O, NR, S or Se; R 2 is
or
ego; R 1 , R 3 , R 21 , R 22, R 23 , X a , X b , R, m, p, s, u and w are the same as defined in formula (I) of claim 1; X 3 is a chlorine atom, bromine atom, iodine atom or leaving group.]
The compound of formula II is reacted with a compound of formula III-B in the presence of copper iodide (CuI) and 2-isobutyrylcyclohexanone to prepare a compound of formula IV-C Process for the preparation of selenazole derivatives of formula (I).

[Formula II]

[Formula III-B]

[Formula IV-C]

[Wherein R 1 , R 2 , R 3 , m and p are the same as defined in formula I of claim 1; X 1 is bromine or iodine.]
A process for preparing the selenazole derivative of formula (I) according to claim 1, wherein the compound of formula (IV) is reacted with an alkyl halogen acetate or alkyl halogen acetic acid alkyl ester to prepare an ester compound of formula (VII).

[Formula IV]

[Formula VII]

[Wherein A, R 1 , R 2 , R 3 , R 4 , R 5 , m and p are the same as defined in formula (I) of claim 1; R 6a is C 1 -C 8 alkyl or allyl.]
A process for preparing the selenazole derivative of formula (I) according to claim 1, characterized by reacting a compound of formula (X) with a compound of formula (III-C) to prepare a compound of formula (VII-D).

[Formula X]

[Formula III-C]

Formula VII-D

[Wherein R 1 , R 2 , R 3 , R 4 , R 5 , m and p are the same as defined in formula (I) of claim 1; R 6a is C 1 -C 8 alkyl or allyl; R 31 is C 1 -C 4 alkylsulfonyl or C 1 -C 4 alkyl substituted or unsubstituted C 6 -C 12 arylsulfonyl.]
The method according to claim 10 or 11, wherein

A process for preparing the selenazole derivative of formula (I) according to claim 1 characterized in that the compound of formula (VIII) is prepared by hydrolyzing an ester compound of formula (VII)

[Formula VII]

[Formula VIII]

[Wherein A, R 1 , R 2 , R 3 , R 4 , R 5 , m and p are the same as defined in formula (I) of claim 1; R 6a is C 1 -C 8 alkyl or allyl; R 6b is a hydrogen atom or an alkali metal, alkaline earth metal or pharmaceutically acceptable organic salt.]
The method according to claim 10 or 11, wherein

Selena of formula I according to claim 1, characterized in that the compound of formula VII is subjected to salt substitution reaction of an allyl ester using a tetrakis (triphenylphosphine) palladium catalyst and a metal salt in an organic solvent. Process for the preparation of sol derivatives.

[Formula VII]

[Formula VIII]

[Wherein A, R 1 , R 2 , R 3 , R 4 , R 5 , m and p are the same as defined in formula (I) of claim 1; R 6a is allyl; R 6b is an alkali metal or alkaline earth metal.]
A treatment and prevention of atherosclerosis or hyperlipidemia comprising the selenazole derivative represented by the formula (I) of claim 1, its hydrate, its solvate, its stereoisomer or its pharmaceutically acceptable salt as an active ingredient, treatment and prevention of hypercholesterolemia Pharmaceutical composition for treating and preventing fatty liver, treating and preventing diabetes, treating and preventing obesity, strengthening muscle, treating and preventing muscle disease, enhancing endurance, improving memory, treating and preventing dementia or Parkinson's disease.
A functional food supplement, a functional beverage, a food additive, and an animal feed composition comprising the selenazole derivative represented by the formula (I) of claim 1, a hydrate thereof, a solvate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
Obesity prevention and obesity improvement, fatty liver prevention and improvement, muscle strengthening, muscle using selenazole derivative represented by the formula (I) of claim 1, hydrate thereof, solvate thereof, stereoisomer thereof or pharmaceutically acceptable salt thereof as an active ingredient Functional cosmetic composition for preventing and ameliorating disease or promoting endurance.
Peroxysome Proliferator Activated Receptor (PPAR) comprising the selenazole derivative represented by the formula (I) of claim 1, a hydrate thereof, a solvate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Activator composition.